Choline esters as absorption-enhancing agents for drug delivery through mucous membranes of the nasal, buccal, sublingual and vaginal cavities

ABSTRACT

Choline esters are used as drug absorption enhancing agents for drugs which are poorly absorbed from the nasal, oral, and vaginal cavities.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a divisional application of U.S. Ser. No. 766,377, filed Aug.16, 1985, now issued to U.S. Pat. No. 4,692,411.

BACKGROUND OF THE INVENTION

The invention relates to a novel method and compositions for enhancingabsorption of drugs from the nasal, buccal, sublingual and vaginalcavities by incorporating therein a choline ester adsorption enhancingagent. The use of choline esters to promote nasal, buccal, sublingualand vaginal drug delivery offers several advantages over attempts toincrease drug absorption from the gastrointestinal tract. Drugs are notexposed to the enzymatic activity of the stomach and small intestine,and are not exposed to the acidic environment of the stomach. This canoffer significant advantages in drug stability.

DESCRIPTION OF THE PRIOR ART

Though the gastrointestinal tract is the preferred route for drugdelivery, all drugs are not well absorbed from this site. In many cases,this may be due to the polar nature or hydrophilic character of thesedrugs. Since they are precluded from rapid absorption, such drugs aresubject to long residency time in the gastrointestinal environment whereboth acidic and enzymatic degradation contribute to their poorbioavailability. It is, therefore, clear that any factor which enhancesthe rate of absorption will demonstrate improved clinical efficacy.Considerable effort has been directed in the recent years towardidentifying agents which increase gastrointestinal absorption of poorlyabsorbed compounds. Surface active agents (George, Sutter, Finegold, J.Infect. Dis. 136, 822 (1977), chelating agents (Cassidy, Tidball, J.Cell Biol. 32, 672 (1967), salicylates (Higuchi, et al., U.S. Pat. No.4,462,991 (1984)), anti-inflammatory agents (Yaginuma et al., Chem.Pharm. Bull. 29, 1974 (1981), phenothiazines (Alexander and Fix, U.S.Pat. No. 4,425,337 (1984) and acyl carnitines (Alexander and Fix, U.S.Ser. No. 606,054) have been shown to increase gastrointestinalpermeability to a variety of compounds.

The present use of choline esters to promote absorption from the nasal,buccal, sublingual and vaginal cavities affords several advantages overthe prior art's non-related absorption promoting compounds. The cholineesters, especially those with medium and long chain fatty acidcomponents, are more potent than the presently used absorption promotingagents. As an example, in aqueous solutions, the choline esters areeffective absorption promoting agents at levels as low as 0.05%. Bycontrast, the effective dose of other known absorption promoters issignificantly higher: sodium salicylate--1%, surfactants--1%, chelatingagents--2%. This difference in potency affords opportunities forreducing the required size of the dosage form and potentially minimizingside effects. The choline esters cause reversible changes in mucosalcell permeability to the target drug, indicating that a permanent changehas not occurred. Other promoting agents, such as the surfactants, causea relatively permanent change in permeability, which is only overcome byturnover of the mucosal cells, a process which may require days forcompletion. Another potential advantage of the choline esters is that,unlike chelating agent such as EDTA, the choline esters may notnecessarily sequester divalent cations (Mg++ or Ca++) which arenecessary for the normal functioning of cells. In other words, there isno tissue damage at concentrations of choline esters which significantlyincrease drug absorption. In contrast to this, studies have indicatedthat surfactant activity, as with sodium lauryl sulfate, is generallyassociated with some degree of cellular damage. This lack of tissuedamage affords a significant advantage to the use of choline esters inpromoting drug absorption across mucosal cells. An added advantage isthat they can be metabolized through normal pathways in the body. Thus,on enzymatic hydrolysis the choline esters produce choline and a fattyacid, both of which are normal endogenous components and nutritiveagents. This eliminates a potential problem from introducing substanceswhich are not normally present in the biochemical pathways of the body(e.g. salicylates, EDTA, etc.).

SUMMARY OF THE INVENTION

It has been found that when poorly absorbed drugs are administered inthe nasal, buccal, sublingual and vaginal cavities, the bioavailabilityof said drugs is increased by administering together with a cholineester absorption enhancing agent.

Accordingly, it is an object of this invention to enhance thebioavailability of poorly absorbed drugs administered in the nasal,buccal, sublingual or vaginal cavities by administering therewith acholine ester absorption enhancing agent.

It is an object of the invention to provide a new dosage form utilizinga class of choline esters which when administered in the nasal, buccal,sublingual or vaginal cavities will provide an increased blood level ofthe therapeutic agent.

Another object of the invention is to provide a choline ester absorptionpromoter of mucous membrane drug absorption at concentrations which donot alter the normal morphology of the mucosal cells.

Still another object of the invention is to provide a choline esterseries of absorption agents that are endogenous and can be metabolizedthrough normal pathways available in the body.

Other objects, features and advantages of the invention will be apparentto those skilled in the art from the detailed description of theinvention which follows.

All of the foregoing objects are readily attained by providing a methodand drug form wherein the absorption of poorly absorbed drugs from thenasal, buccal, sublingual and vaginal cavities is enhanced. The methodcomprises the steps of preparing a dosage form suitable for nasal,buccal, sublingual or vaginal delivery, said dosage form comprising aneffective unit dosage amount of the poorly absorbed drug, a cholineester absorption-enhancing agent or pharmaceutically acceptable saltthereof, the agent being present in said dosage form in an amountsufficient to be effective in enhancing the rate of the mucosal membraneabsorption of the therapeutic agent, and pharmaceutically acceptableexcipients.

DETAILED DESCRIPTION OF THE INVENTION

The present invention generally comprises the steps of preparing adosage form capable of being administered in the nasal, buccal,sublingual or vaginal cavities, wherein the dosage form comprises aneffective unit dosage amount of a poorly absorbed drug and a cholineester absorption enhancing agent, the choline ester being present in thedosage form in a sufficient quantity to be effective in enhancing mucousmembrane absorption rates and administering the dosage form towarm-blooded animals. The amount of poorly absorbed drug varies over awide range, but generally the thermapeutically effective unit dosageamount of the selected poorly absorbed drug depends on that amount knownin the art to obtain the desired results.

The compounds that are used as absorption enhancers in our method anddrug forms are fatty acid esters of choline and pharmaceuticallyacceptable salts thereof, of the formula:

    [(CH.sub.3).sub.3 N.sup.+ CH.sub.2 CH.sub.2 OR]X.sup.-

wherein R is:

(a) C₂ --C₂₀ saturated acyl such as hexanoyl, octanoyl, decanoyl,lauroyl, myristoyl, palmitoyl, stearoyl and the like;

(b) C₂ --C₂₀ acyl with 1 to 6 double bonds such as 2-hexenoyl,9-decenoyl, 9-hexadecenoyl (palmitoleoyl), oleoyl, myristoleoyl,9,12-hexadecadienoyl, α-linoleoyl, γ-linolenoyl, arachidyl and the like;

(c) C₂ --C₂₀ hydroxyacyl with 1 to 3 hydroxy groups such as2-hydroxylauroyl, 2-hydroxymyristoyl, 2-hydroxypalmitoyl and the like;

(d) C₄ --C₂₀ ketoacyl such as 6-ketodecanoyl,4-keto-9,11,13-octadecatrienoyl and the like;

(e) C₅ --C₂₀ unsaturated hydroxyacyl such as 2-hydroxy-12-octadecenoyland the like;

(f) C₅ --C₂₀ carbalkoxyacyl such as ω-ethoxycarbonyloctanoyl and thelike;

(g) arylacyl (C₇ --C₂₀) such as phenylacetyl and the like;

(h) alkylaroyl (C₇ --C₂₀) such as butylbenzoyl and the like;

(i) carboxyacyl (C₅ --C₂₀) such as sebacyl; and X is a pharmaceuticallyacceptable counterion such as chloride, sulfate, nitrate, perchlorate,bromide, iodide phosphate, acetate, benzoate, tartrate, citrate,propionate, gluconate, lactate, maleate, fumarate, bezylate, camsylate,esylate, gluceptate, mesylate, napsylate and the like.

The preferred mucous membrane absorption enhancing agents of the aboveformula are:

1. hexanoylcholine

2. lauroylcholine

3. octanoylcholine

4. decanoylcholine

5. myristoylcholine

6. palmitoylcholine

7. stearoylcholine

8. 2-hexenoylcholine

9. 9-decenoylcholine

10. 9-hexadecenoylcholine

11. α-lineoylcholine

12. 2-hydroxylauroylcholine

13. 6-ketodecanoylcholine

14. ω-ethoxycarbonyloctanoylcholine

15. 2-hydroxypalmitoylcholine

The most preferred absorption enhancing agents useful in our method anddosage forms are:

1. hexanoylcholine

2. octanoylcholine

3. decanoylcholine

4. lauroylcholine

5. myristoylcholine

6. palmitoylcholine

7. stearoylcholine

8. decanoylcholine

and pharmaceutically acceptable salts of the above.

The choline ester absorption enhancing agents employed in the practiceof this invention are known compounds which are commercially availableand processes for their preparation are disclosed throughout the art.

Various active agents provide beneficial effects when administered topatients. Such agents which can be made more useful by enhancing theirabsorption in accordance with this invention, are exemplified by, butnot limited to, the following classes of drugs:

(1) β-lactam antibiotics such as cefoxitin, N-formamidinylthienamycin,amoxicillin, ampicillin, azlocillin, bacampicillin, carbenicillin,cefaclor, cefadroxil, cefamandole, cefatrizine, cefazoline, cefonicid,cefaperazone, ceforanide, cefotaxime, cefotiam, cefroxadine, cefsulodin,ceftazidime, ceftizoxime, cephalexin, cephaloglycin, cephaloridine,cephradine, cyclacillin, cloxacillin, dicloxacillin, floxacillin,hetacillin, methicillin, nafcillin, oxacillin, sarmoxacillin,sarpicillin, talampicillin, ticaricillin, penicillin G., penicillin V.,pivampicillin, piperacillin, pirbenicillin and the like.

(2) Aminoglycoside antibiotics such as gentamicin, amikacin, astromicin,betamicin, butikacin, butirosin, clindamycin, josamycin, kanamycin,neomycin, netilmicin, tobramycin and the like.

(3) Antiviral agentssuch as ara C (cytarabine), acyclovir, floxuridine,ribavirin, vidarabine, idoxuridine, trifluridine and the like.

(4) Amino acids such as methyldopa, carbidopa, levodopa, fludalanine,γ-aminobutyric acid and the like.

(5) Smooth muscle relaxants such as theophylline, aminophylline,diphylline, oxtriphylline, ambuphylline, fenethylline, guathylline,pentoxyfylline, xanthinol niacinate, theophylline glycinate,glucophylline and the like.

(6) Polypeptides such as cyclo(N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe)acetate(L-363,586), somatostatin, insulin, gastrin, caerulein, cholecystokinin,atrial natriuretic factor, and the like.

(7) Anti-inflammatory agents such as indomethacin, sulindac, ibuprofenand the like.

(8) Diuretics such as aldactone, hydrochlorothiazide, amiloride,chlorothiazide, furosemide and the like.

The enhancement of drug absorption in accordance with this invention isnot by any means limited to the above drugs, but are in generalapplicable to other classes of drugs such as analgesics, anabolics,androgens, anorexics, adrenergics, antiadrenergics, antiallergics,anti-bacterials, anticholinergics, antidepressants, antidiabetics,antifungal agents, antihypertensives, antineoplastics, antipsychotics,sedatives, cardiovascular agents, antiulcer agents, anticoagulants,anthelmintics, radio-opaques, radionuclide diagnostic agents and thelike.

Generally, the amount of adjuvant employed in the practice of theinvention ranges from 0.05-500 mg in each dose. The percentage ofadjuvant in the total combination of drug plus adjuvant is 0.05-50% witha preferred ratio of adjuvant in the total combination of adjuvant plusdrug being 0.05-25%.

For nasal administration, the formulations may be prepared as drops,sprays, mists, aerosols, gels, and other standard procedures known inthe art. The preferred formulation is a liquid drop composed of aminimum of 1 mg choline ester with the pharmacologically required doseof drug and sufficient excipients to formulate an acceptablecomposition. For oral application, the formulations may be prepared asgels, suspensions, polymers, tablets, and other standard proceduresknown in the art. The preferred formulation is a compressed tabletcomposed of a minimum of 1 mg choline ester with the pharmacologicallyrequired dose of drug and sufficient excipients to formulate anacceptable composition. For vaginal administration, the formulations maybe prepared as solutions, suspensions, gels, suppositories, tablets, andother standard procedures known in the art. The preferred formulation isa solid suppository composed of a minimum of 1 mg choline ester with thepharmacologically required dose of drug and sufficient suppository baseto formulate an acceptable composition. The methods and choice ofexcipients and suppository bases are well known to those skilled in theart and the composition of said formulations is not limited to liquiddrops, compressed tablets or solid suppositories by this invention.

The following examples illustrate preparation of various compositions ofthe invention. The examples should be construed as illustrations ratherthan limitations thereof.

EXAMPLE 1

Effect of palmitoylcholine iodide on the nasal, buccal and vaginalabsorption of α-methyldopa (amino acid, antihypertensive). Experimentswere performed with rats wherein each animal received an aqueousformulation administered to the nasal, oral or vaginal cavities. Theformulations contained the indicated amount of α-methyldopa in thepresence or absence of 1.0 mg palmitoylcholine iodide. Procedures weretested to eliminate the possibility of cross-contamination between thenasal and oral cavities. Blood levels of α-methyldopa were determined byhigh performance liquid chromatography and the amount of drug absorbed(percent bioavailability) calculated against intravenous α-methyldopaadministration.

    ______________________________________                                                              Percent α-methyldopa Bio-                                               availability in the Absence                                       Dose of     (-) or Presence (+) of                                  Administra-                                                                             α-methyl-                                                                           Palmitoylcholine*                                       tion Route                                                                              dopa (mg)   (-)       (+)                                           ______________________________________                                        Nasal Cavity                                                                            0.5         7 ± 1.1                                                                               86 ± 16.3                                 Oral Cavity                                                                             2.5         3 ± 0.7                                                                               5 ± 0.5                                   Vaginal Cavity                                                                          2.5         2 ± 1.0                                                                              55 ± 2.0                                   ______________________________________                                         *Values represent the mean ± SD for n = 3 determinations.             

EXAMPLE 2

Effect of palmitoylcholine iodide on the nasal, buccal and vaginalabsorption of cefoxitin (β-lactam antibiotic). Experiments wereperformed with rats wherein each animal received an aqueous formulationadministered to the nasal, oral or vaginal cavities. The formulationscontained 2.5 mg sodium cefoxitin in the presence or absence of 1.0 mgpalmitoylcholine iodide. Procedures were tested to eliminate thepossibility of cross-contamination between the nasal and oral cavities.Blood levels of cefoxitin were determined by high performance liquidchromatography and the amount of drug absorbed (percent bioavailability)calculated against intravenous cefoxitin administration.

    ______________________________________                                                       Percent cefoxitin Bio-                                                        availability in the Absence                                                   (-) or Presence (+) of                                         Administra-    Palmitoylcholine*                                              tion Route     (-)        (+)                                                 ______________________________________                                        Nasal Cavity   15 ± 9.3                                                                              67 ± 17                                          Oral Cavity    0.4 ± 0.6                                                                             0.3 ± 0.5                                        Vaginal Cavity   2 ± 3.8                                                                              38 ± 3.1                                        ______________________________________                                         *Values represent the mean ± SD for n = 3 determinations.             

What is claimed is:
 1. A pharmaceutical composition for enhancingabsorption from the nasal, buccal, sublingual or vaginal cavitiescomprising a therapeutically effective dosage amount of an amino acidselected from the group consisting of methyldopa, carbidopa, levodopa,fludalanine and α-aminobutyric acid or a polypeptide selected from thegroup consisting of cyclo(N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe) acetate,somatostatin, insulin, gastrin, caerulein, cholecystokinin and atrialnatriuretic factors and a choline ester absorption enhancing agent ofthe formula:

    [(CH.sub.3).sub.3 N.sup.+ CH.sub.2 CH.sub.2 OR]X.sup.-

wherein R is saturated acyl (C₂ --C₂₀), acyl(C₂ --C₂₀ with 1 to 6 doublebonds, hydroxyacyl (C₂ --C₂₀) with 1 to 3 hydroxy groups, ketoacyl (C₄--C₂₀), unsaturated hydroxyacyl (C₅ --C₂₀), carboxyacyl (C₄ --C₂₀),arylacyl (C₇ --C₂₀) alkylaroyl (C₇ --C₂₀) or carbalkoxyacyl (C₅ --C₂₀)and X is a pharmaceutically acceptable counterion.
 2. The composition ofclaim 1, wherein said amino acid is methyldopa, carbidopa or levodopaand said polypeptide is cyclo(N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe) acetate,somatostatin, insulin or atrial natriretic factor and the choline esterabsorption enhancing agent is selected from the group consisting ofhexanoylcholine, decanoylcholine, lauroylcholine, octanoylcholine,myristoylcholine, palmitoylcholine, stearoylcholine, 2-hexenoylcholine,9-decenoylcholine 9-hexadecenoylcholine, α-lineoylcholine,2-hydroxylauroylcholine, 2-hydroxymyristoylcholine,6-ketodecanoylcholine, 12-hydroxy-12-octadecanoylcholine,ω-ethoxycarbonyloctanoylcholine and 2-hydroxypalmitoylcholine.
 3. Thecomposition of claim 2, wherein said amino acid is methyldopa orlevodopa and said polypeptide is cyclo(N-Me-Ala-Tyr-Lys-Val-Phe)acetate, atrial natriuetic factor, insulin or somatostatin and saidenhancing agent is lauroylcholine, myristoylcholine, stearoylcholine orpalmitolycholine.
 4. The composition of claim 3, wherein said amino acidis methyldopa and said polypeptide is insulin said enhancing agent ispalmitoylcholine.
 5. The composition of claim 4, wherein said amino acidis α-methyldopa.
 6. A method of enhancing the rate of absorption of anamino acid drug selected from the group consisting of methyldopa,carbidopa, levodopa, fludalanine and Υ-aminobutyric acid or apolypeptide drug selected from the group consisting ofcyclo(N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe) acetate, somatostatin, insulin,gastrin, caerulein, cholecystokinin and atrial natriuretic factorsadministered to the nasal, buccal, sublingual or vaginal cavities, whichcomprises administering a composition comprising a therapeuticallyeffective dosage amount of said drug and a choline ester absorptionenhancing agent of the formula:

    [(CH.sub.3).sub.3 N.sup.+ CH.sub.2 CH.sub.2 OR]X.sup.-

wherein R is saturated acyl (C₂ --C₂₀), acyl (C₂ --C₂₀) with 1 to 6double bonds, hydroxyacyl (C₂ --C₂₀) with 1 to 3 hydroxy groups,ketoacyl (C₄ --C₂₀), unsaturated hydroxyacyl (C₅ --C₂₀), carboxyacyl (C₄--C₂₀) arylacyl (C₇ --C₂₀), alkylaroyl (C₇ --C₂₀) or carbalkoxyacyl (C₅--C₂₀) and X is a pharmaceutically acceptable counterion.
 7. The methodof claim 6, wherein said amino acid is methyldopa, carbidopa or levodopaand said polypeptide is cyclo(N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe) acetate,somatostatin, insulin or atrial natriuretic factor and said cholineester absorption enhancing agent is selected from the group consistingof hexanoylcholine, decanoylcholine, lauroylcholine, octanoylcholine,myristoylcholine, palmitoylcholine, stearoylcholine, 2-hexenoylcholine,9-decenoylcholine, 9-hexadecenoylcholine, α-lineoylcholine,2-hydroxylauroylcholine, 2-hydroxymyristoylcholine,6-ketodecanoylcholine, 12-hydroxy-12-octadecanoylcholine,ω-ethoxycarbonyloctanoylcholine and 2-hydroxypalmitoylcholine.
 8. Themethod of claim 7, wherein said polypeptide iscyclo(N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe) acetate somatostatin, or atrialnatriuretic factor and the enhancing agent is hexanoylcholine,octanoylcholine, decanoylcholine, lauroylcholine, myristoylcholine,palmitoylcholine or stearoylcholine.
 9. The method of claim 8, whereinsaid enhancing agent is palmitoylcholine.
 10. The composition of claim 1further comprising pharmaceutically acceptable excipients.
 11. Themethod of claim 8, wherein the enhancing agent is palmitoylcholine. 12.The method of claim 7, wherein the amino acid ismethyldopa or levodopaand the enhancing agent is palmitoylcholine.
 13. The method of claim 12,wherein the amino acid is α-methyldopa.
 14. The method of claim 9,wherein the popypeptide is cyclo(N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe)acetate.
 15. The method of claim 9, wherein the polypeptide is atrialnatriuretic factor.